CNO Report # 240

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CNO Report # 240

Release Date  03 FEB 2017

Draft Report Compiled by

Ralph Turchiano




In This Issue:

1.       Gastric acid suppressants linked to hospitalization

2.       Workouts with fewer reps could yield better results

3.       A natural compound can block the formation of toxins associated with Parkinson’s disease

4.       Protein isolated from baker’s yeast shows potential against leukemia cells

5.       Millions of people with metabolic syndrome may need more vitamin E. Conventional vitamin E blood tests as they are now being done are useless.

6.       Getting fit, getting enough iron boosts students’ grades, study suggests

7.       Anti-inflammatory diet could reduce risk of bone loss in women

8.       Anticancer properties of mono/di-halogenated coumarins

9.       Antibiotics can boost bacterial reproduction

10.   Yeast mutants unlock the secrets of aging

11.   Vitamin C may decrease the risk of atrial fibrillation after cardiac surgery

12.   Vitamin D discovery could prove key to new treatments

13.   Pilot study highlights role of grapes in preventing Alzheimer’s disease


Public Release: 11-Jan-2017

Gastric acid suppressants linked to hospitalization

Sax Institute

New research has found a link between popular heartburn drugs and an increase in the risk of infectious gastroenteritis — an illness that results in 13.1 million lost days of work in Australia a year.

The study led by The Australian National University (ANU) and based on data from the Sax Institute’s 45 and Up Study, found people who take proton pump inhibitors (PPIs), had a 70 per cent increase in the risk of being admitted to hospital with infectious gastroenteritis.

Lead author Dr Yingxi Chen from the ANU National Centre for Epidemiology and Population Health said the research examined data from the study to look at cases of infectious gastroenteritis in Australians older than 45.

“We found that taking PPIs increased the risk of hospitalisation with infectious gastroenteritis by up to 70 per cent because they significantly reduce the amount of acid made by stomach, which increases risk of infectious gastro,” Dr Chen said.

PPIs are one of the world’s most commonly used gastric acid suppressants, with more than 19 million scripts prescribed annually in Australia.

The research builds on a report by the ANU National Centre for Epidemiology and Population Health which found 15.1 million gastro cases in Australia in 2010.

“There is no doubt that PPIs are an effective treatment for reflux and heartburn. However, clinicians and the patients using them should be fully aware of the side effects when considering PPI use and dosage,” Dr Chen said.

“The elderly and those with chronic bowel problems are most at risk. These patients should be having a conversation with their doctor to ensure that they are on right dose and that these drugs are the right fit for them.”

Dr Martin McNamara, Head of Research Assets at the Sax Institute said these findings demonstrated the value of the 45 and Up Study as a national research resource.

“The 45 and Up Study is the largest ongoing study of healthy ageing in the Southern Hemisphere, allowing hundreds of Australia’s world class researchers to investigate big and complex issues and deliver answers in ways that are easily accessible to policy makers,” he said.

Public Release: 13-Jan-2017

Workouts with fewer reps could yield better results

University of Stirling

Time-poor people who do fewer repetitions during high-intensity interval training (HIIT) workouts may get better fitness benefits than those who complete more, according to a University of Stirling analysis.

Experts from Scotland’s University for Sporting Excellence have reviewed existing studies that investigate the benefits of regularly performing repetitions of a special type of high-intensity cycle sprint known as ‘supramaximal’. They found doing fewer repetitions of these sprint intervals on a bike may lead to greater improvements in cardiorespiratory fitness.

Dr Niels Vollaard, Lecturer in Health and Exercise Science in the Faculty of Health Sciences and Sport, said: “Lack of time is frequently cited as one of the main barriers to people becoming or staying physically active. High-intensity workouts have begun to tackle this problem, allowing people to get maximum health benefits while working out for a shorter time.

“We found improved cardiorespiratory fitness does not suffer when people complete fewer sprint repetitions and that this may even produce better results. The optimal number of repetitions appears to be just two, so workouts based on supramaximal sprints can be kept very short without compromising on the results.”

The findings of this research are only applicable to ‘supramaximal’ exercise, which requires specialised exercise bikes that enable very high exercise intensities. Whether HIIT workouts at lower intensities also benefit from a low number of sprint repetitions is not yet known.

Previously, it has been assumed that performing more repetitions of high-intensity exercise will produce greater improvements in cardiorespiratory fitness.

In this analysis, published in the leading journal Medicine and Science in Sports and Exercise, scientists found that after performing two maximal sprints, each additional sprint in a training session reduced the overall improvement in fitness by around 5% on average.

Dr Vollaard added: “For the first time, we have evidence to suggest an indicator of fitness levels is improved more by doing fewer repetitions of high-intensity exercise. We are currently performing studies to investigate the physiological mechanisms that may explain this unexpected finding.

“To encourage more people to become active and help increase the health of the population, we need to investigate the optimal duration and number of sprint intervals people could undertake on a bike, while getting the same benefits as longer sessions.”

Fitness levels were measured by VO2max, the maximal amount of oxygen the body is capable of utilising in one minute, which is accepted as one of the best indicators of future health and risk of premature death. However, studying other indicators of health and fitness, including blood pressure and insulin sensitivity, will give a fuller picture of how the body responds to different types of HIIT workouts.

Public Release: 16-Jan-2017

A natural compound can block the formation of toxins associated with Parkinson’s disease

Squalamine, a natural product studied for its anticancer and anti-infective properties, could also lead to future treatments for Parkinson’s disease

St John’s College, University of Cambridge

A naturally-occurring compound has been found to block a molecular process thought to underlie Parkinson’s Disease, and to suppress its toxic products, scientists have reported.

The findings, although only preliminary, suggest that the compound, called squalamine, could be exploited in various ways as the basis of a potential treatment for Parkinson’s Disease. The compound has previously been used in clinical trials for cancer and eye conditions in the United States, and a trial in Parkinson’s Disease patients is now being planned by one of the researchers involved in the study.

Squalamine is a steroid which was discovered in the 1990s in dogfish sharks, although the form now used by scientists is a safer, synthetic analogue. To date, it has been extensively investigated as a potential anti-infective and anticancer therapy.

But in the new study, researchers discovered that squalamine also dramatically inhibits the early formation of toxic aggregates of the protein alpha-synuclein – a process thought to start a chain reaction of molecular events eventually leading to Parkinson’s Disease. Remarkably, they also then found that it can suppress the toxicity of these poisonous particles.

The researchers tested squalamine in both cell cultures in the lab, and in an animal model using nematode worms. While their findings therefore only represent a step towards a treatment for Parkinson’s Disease in humans, they described the results as representing significant progress.

The study was led by academics from the Centre for Misfolding Diseases, based in the Chemistry Department at the University of Cambridge in the United Kingdom, and Georgetown University and the National Institutes of Health in the United States. Scientists from the Netherlands, Italy and Spain also played key roles. The findings are published in Proceedings of The National Academy of Sciences.

Professor Christopher Dobson, who is one of the authors and Master of St John’s College, as well as a Professor in the Chemistry Department at the University of Cambridge, said: “To our surprise, we found evidence that squalamine not only slows down the formation of the toxins associated with Parkinson’s Disease, but also makes them less toxic altogether.”

“If further tests prove to be successful, it is possible that a drug treating at least some of the symptoms of Parkinson’s Disease could be developed from squalamine. We might then be able to improve on that incrementally, by searching for better molecules that augment its effects.”

Professor Michele Vendruscolo, from the Department of Chemistry at the University of Cambridge and a co-author, said: “This is an encouraging step forward in our efforts to discover potential drugs against Parkinson’s Disease. Squalamine can prevent alpha-synuclein from malfunctioning, essentially by normalising its binding to lipid membranes. If there are going to be ways to beat the disease, it seems likely that this is one that may work.”

The study stemmed from research led by Dr Michael Zasloff, professor of surgery and pediatrics at Georgetown University School of Medicine in the USA. Zasloff, who also co-authored the latest study, discovered squalamine in 1993 and has since led extensive work exploring its potential as a treatment for conditions including cancer.

In the new study, the researchers explored squalamine’s capacity to displace alpha-synuclein from cell membranes – a phenomenon that was first observed in the laboratory headed by another co-author, Dr Ad Bax, in the National Institutes of Health in Bethesda, USA. This finding has significant implications for Parkinson’s Disease, because alpha-synuclein works by binding to the membranes of tiny, bubble-like structures called synaptic vesicles, which help to transfer neurotransmitters between neurons.

Under normal circumstances, the protein thus aids the effective flow of chemical signals, but in some instances, it malfunctions and instead begins to clump together, creating toxic particles harmful to brain cells. This clustering is the hallmark of Parkinson’s Disease.

The researchers carried out a series of experiments which analysed the interaction between squalamine, alpha-synuclein and lipid vesicles, building on earlier work from Cambridge scientists which showed the vital role that vesicles play in initiating the aggregation. They found that squalamine inhibits the aggregation of the protein by competing for binding sites on the surfaces of synthetic vesicles. By displacing the protein in this way, it significantly reduces the rate at which toxic particles form.

Further tests, carried out with human neuronal cells, then revealed another key factor – that squalamine also suppresses the toxicity of these particles.

Finally, the group tested the impact of squalamine in an animal model of Parkinson’s Disease, by using nematode worms genetically programmed to over-express alpha-synuclein in their muscle cells. As the worms develop, alpha-synuclein aggregation causes them to become paralysed, but squalamine prevented the paralysis from taking effect. “We could literally see that the oral treatment of squalamine did not allow alpha-synuclein to cluster, and prevented muscular paralysis inside the worms,” Zasloff said.

Together, the results imply that squalamine could be used as the basis of a treatment targeting at least some of the symptoms of Parkinson’s Disease. Zasloff says he is now planning a clinical trial with squalamine in Parkinson’s Disease patients in the US.

Further research is, however, needed to determine what the precise benefits of squalamine would be – and what form any resulting drug might take. In particular, it is not yet clear whether squalamine can reach the specific regions of the brain where the main molecular processes determining Parkinson’s Disease take place.

The researchers suggest that it would be particularly interesting to start investigating the efficacy of squalamine as a means to alleviate certain symptoms. If taken orally, for instance, the compound may perhaps relieve the severe constipation many patients experience, by targeting the gastrointestinal system and affecting alpha-synuclein in the gut.

It is also conceivable that a treatment of that sort could “cascade” signals to other parts of the body. “Targeting alpha-synuclein in the gut may perhaps in some cases be sufficient to delay the progress of other aspects of Parkinson’s Disease, at least for symptoms concerning the peripheral nervous system,” Vendruscolo said.

“In many ways squalamine gives us a lead rather than a definitive treatment,” Professor Dobson added. “Parkinson’s Disease has many symptoms and we hope that either this compound, or a derivative of it with a similar mechanism of action, could alleviate at least some of them.”

“One of the most exciting prospects is that, subject to further tests, we might be able to use it to make improvements to patients’ lives, while also studying other compounds with the aim of developing a more powerful treatment in the future.”

Public Release: 17-Jan-2017

Protein isolated from baker’s yeast shows potential against leukemia cells

Researchers performed in vitro trials to test the effect of L-asparaginase on acute lymphoblastic leukemia cells and published the results in Scientific Reports

Fundação de Amparo à Pesquisa do Estado de São Paulo

An enzyme identified in Saccharomyces cerevisiae, commonly known as brewer’s or baker’s yeast, has passed in vitro trials, demonstrating its capacity to kill acute lymphoblastic leukemia (ALL) cells.

Characterized by malignant alterations in the blood-forming stem cells in the bone marrow, ALL is the most common form of childhood cancer.

Findings from the research project are described by scientists at the University of São Paulo’s School of Pharmaceutical Sciences (FCF-USP) and São Paulo State University’s Coastal Campus Bioscience Institute (IB-CLP-UNESP) in an article published in the journal Scientific Reports.

“In this study we characterize the enzyme L-asparaginase from S. cerevisiae. The results show this protein can efficiently annihilate leukemia cells with low cytotoxicity to healthy cells,” said Gisele Monteiro, a professor at FCF-USP and the principal investigator for the published study.

Production of the enzyme asparagine synthetase is deficient in ALL and several other types of cancer cells, which are therefore unable to synthesize the amino acid asparagine.

“This type of cell depends on extracellular sources of asparagine, an essential amino acid for the synthesis of proteins and hence of DNA and RNA. So it’s required for cell division,” Monteiro said. “The enzyme asparaginase depletes this amino acid in the extracellular medium, converting it into aspartate and ammonia. In patients with ALL, this leads to a sharp fall in serum levels of asparagine, hindering protein synthesis in malignant cells and inducing apoptosis, or programmed cell death.”

According to Monteiro, since the 1970s, ALL has been treated using an enzyme similar to the L-asparaginase described in the study but extracted from the bacterium Escherichia coli. When administered with other medications, treatment with the bacterial enzyme can achieve a remission rate of up to 80%. However, about 25% of patients have immune responses ranging from mild allergy to anaphylactic shock and are unable to use the biopharmaceutical as a result.

As an alternative, two other drugs in the same class are internationally commercially available. One is PEG-asparaginase, a version of E. coli asparaginase that has been chemically modified to extend the drug’s effect by reducing excretion by the kidneys and formation of antibodies against the protein. As a result, the dose can be reduced, and adverse side effects are mitigated. The other similar drug, marketed as Erwinase, is also based on the enzyme asparaginase but is extracted from the bacterium Erwinia chrysanthemi.

“Our goal in this project wasn’t to produce the enzyme, but rather to find a new source of the biodrug in microorganisms for use in patients who develop resistance to the bacterial enzyme,” Oliveira said.

To this end, the researchers isolated fungi from several different Brazilian environments, such as the Cerrado and Caatinga, as well as marine and land environments in Antarctica. According to Oliveira, these organisms often secrete asparaginase into the extracellular medium in response to a shortage of nitrogen. “This lowers the cost of purifying the molecule for drug production, an important factor from an industrial standpoint,” he said.

The group also used bioinformatics tools to mine information on the genomes of several microorganisms from international databases. In this manner, they identified a gene responsible for producing an enzyme that closely resembles the enzymes found in E. coli and E. chrysanthemi, but with a number of advantages, in the genome of S. cerevisiae.

According to Iris Munhoz Costa, the first author of the study, many essential cellular processes are same in yeast and humans. This is because yeast is eukaryotic: its cells have a membrane-bound nucleus that contains the genetic material, whereas bacteria are prokaryotic and do not. This is believed to be why L-asparaginase induces a more moderate immune response than bacterial enzymes do.

The gene of interest from L-asparaginase was cloned, and the researchers used genetic engineering to make E. coli express large amounts of the enzyme originally found in yeast.

“We were able to obtain the recombinant protein,” Costa said. “We then performed studies to characterize its secondary structure and identify important regions called catalytic sites. Finally, we evaluated its efficacy in vitro.”

The enzyme was tested in three different cell lineages: leukemia cells incapable of producing asparagine at normal levels (MOLT4); another line of leukemia cells, in this case capable of producing asparagine at normal levels (REH); and non-malignant cells, used as a control (HUVECs).

These three different cell lineages were subdivided into two groups. One was treated with the commercially available E. coli enzyme, and the other was treated with L-asparaginase from yeast.

“The bacterial enzyme killed about 90% of the MOLT4 human leukemia cells and displayed low toxicity to the healthy HUVEC cells, killing only 10%,” Monteiro said. “The yeast enzyme killed between 70% and 80% of the MOLT4 cells and displayed less than 10% toxicity for HUVEC cells. Neither was significantly effective against REH cells.”

In her view, the results are encouraging, in contrast with those of studies performed with the same enzyme in the 1970s. At that time, the tests involved a version of the protein extracted directly from yeast and containing many impurities.

The group’s next step is to perform new in vitro trials with different cell types to evaluate the immune response and toxicity. If the results are positive, the first tests in animals may be next. The researchers are also studying possible modifications that could be made to the molecule’s structure to increase anti-tumor activity and extend the enzyme’s half-life.

In addition to ALL, asparaginase is also used to treat rarer cancers such as lymphosarcoma, Hodgkin’s disease, chronic lymphocytic leukemia, reticulosarcoma and melanosarcoma.

Millions of people with metabolic syndrome may need more vitamin E. Conventional vitamin E blood tests as they are now being done are useless.

Public Release: 17-Jan-2017


“This basically means that conventional vitamin E blood tests as they are now being done are useless.”

Oregon State University


CORVALLIS, Ore. – New research has shown that people with metabolic syndrome need significantly more vitamin E – which could be a serious public health concern, in light of the millions of people who have this condition that’s often related to obesity.

A study just published in the American Journal of Clinical Nutrition also made it clear that conventional tests to measure vitamin E levels in the blood may have limited accuracy compared to tests made in research laboratories, to the point that conventional tests can actually mask an underlying problem.

Vitamin E – one of the more difficult micronutrients to obtain by dietary means – is an antioxidant important for cell protection. It also affects gene expression, immune function, aids in repair of wounds and the damage of atherosclerosis, is important for vision and neurologic function, and largely prevents fat from going rancid.

Nutrition surveys have estimated that 92 percent of men and 96 percent of women in the United States fail to get an adequate daily intake of vitamin E in their diet. It is found at high levels in almonds, wheat germ, various seeds and oils, and at much lower levels in some vegetables and salad greens, such as spinach and kale.

This study was done by researchers in the Linus Pauling Institute at Oregon State University and the Human Nutrition Program at The Ohio State University, as a double-blind, crossover clinical trial focusing on vitamin E levels in people with metabolic syndrome. It was supported by the National Institutes of Health, the National Dairy Council and DSM Nutrition.

“The research showed that people with metabolic syndrome need about 30-50 percent more vitamin E than those who are generally healthy,” said Maret Traber, a professor in the OSU College of Public Health and Human Sciences, and Ava Helen Pauling Professor in the Linus Pauling Institute.

“In previous work we showed that people with metabolic syndrome had lower bioavailability of vitamin E. Our current work uses a novel approach to measure how much vitamin E the body needs. This study clearly demonstrates that people with metabolic syndrome need a higher intake of this vitamin.”

More than 30 percent of the American public are obese, and more than 25 percent of the adults in the United States meet the criteria for metabolic syndrome, putting them at significantly increased risk for cardiovascular disease and type-2 diabetes – primary causes of death in the developed world.

That syndrome is defined by diagnosis of three or more of several conditions, including abdominal obesity, elevated lipids, high blood pressure, pro-inflammatory state, a pro-thrombotic state and insulin resistance or impaired glucose tolerance.

This research, for the first time, also clearly outlined a flaw with conventional approaches to measuring vitamin E.

By “labeling” vitamin E with deuterium, a stable isotope of hydrogen, scientists were able to measure the amount of the micronutrient that was eliminated by the body, compared to the intake. The advanced research laboratory tests, which are not available to the general public, showed that people with metabolic syndrome retained 30-50 percent more vitamin E than healthy people – showing that they needed it. When the body doesn’t need vitamin E, the excess is excreted.

But in the group with metabolic syndrome, even as their tissues were taking up and retaining the needed vitamin E, their blood levels by conventional measurement appeared about the same as those of a normal, healthy person.

“We’ve discovered that vitamin E levels often look normal in the blood, because this micronutrient is attracted to high cholesterol and fat,” Traber said. “So vitamin E can stay at higher levels in the circulatory system and give the illusion of adequate levels, even as tissues are deficient.

“This basically means that conventional vitamin E blood tests as they are now being done are useless.”

The findings support the conclusion that people with metabolic syndrome have higher levels of oxidative and inflammatory stress, scientists said in their conclusion, and require more antioxidants such as vitamins E as a result.

Public Release: 25-Jan-2017

Getting fit, getting enough iron boosts students’ grades, study suggests

Researchers at Nebraska, Penn State find link between GPA, fitness and iron levels

University of Nebraska-Lincoln

Researchers at the University of Nebraska-Lincoln and Pennsylvania State University have found that a student’s fitness level and iron status could be the difference between making an A or a B.

In the study based at Penn State, evidence suggested female college students who were fit and had normal iron levels achieved higher grade point averages than unfit women who were iron deficient. The difference in grade point average was as much as 0.34 — enough to drop or increase a letter grade.

“GPA is a very easy measure of success and something everyone can relate to,” said Karsten Koehler, assistant professor of nutrition and health sciences at Nebraska. “That’s something that resonates pretty well. It’s always nice to show an association that has a meaningful effect that translates into something everybody can apply.”

Iron helps the body with essential functions such as transporting oxygen in the blood. Iron deficiency is associated with fatigue, lower work capacity and poor academic performance. Physical fitness is also known to influence overall health, cognition and learning. Koehler and his colleagues wanted to explore the lesser known combined effects of fitness and iron deficiency on grade point average.

The 105 women analyzed were all enrolled at Penn State and had an average GPA of 3.68. Data showed that women with the highest levels of stored iron had the highest grades. In addition, those who were fittest and had adequate iron stores had higher grades than less-fit women with lower iron stores.

Koehler, who is also conducting research on the relationship between iron and athletic performance in adolescents in Nebraska, says that the impact of fitness was greater overall than the impact of iron status, but taken together, the impact was even greater.

“Improving fitness or maintaining a high level of fitness can be important for collegiate success,” said Koehler. “Ideally, we should also make sure the diet is appropriate to prevent nutrient deficiencies.”

An unfit person who makes good on a New Year’s resolution will not suddenly improve their GPA, Koehler said, “but there’s profound evidence that it goes hand-in-hand–that training has an effect on cognitive performance.”

The study was published in January’s edition of The Journal of Nutrition and is available online.

Public Release: 26-Jan-2017

Anti-inflammatory diet could reduce risk of bone loss in women

Study also found diet linked to fewer hip fractures in younger white women

Ohio State University

COLUMBUS, Ohio – Anti-inflammatory diets — which tend to be high in vegetables, fruits, fish and whole grains — could boost bone health and prevent fractures in some women, a new study suggests.

Researchers examined data from the landmark Women’s Health Initiative to compare levels of inflammatory elements in the diet to bone mineral density and fractures and found new associations between food and bone health. The study, led by Tonya Orchard, an assistant professor of human nutrition at The Ohio State University, appears in the Journal of Bone and Mineral Research.

Women with the least-inflammatory diets (based on a scoring system called the Dietary Inflammatory Index) lost less bone density during the six-year follow-up period than their peers with the most-inflammatory diets. This was despite the fact that they started off with lower bone density overall.

Furthermore, diets with low inflammatory potential appeared to correspond to lower risk of hip fracture among one subgroup of the study — post-menopausal white women younger than 63.

The findings suggest that women’s bone health could benefit when they choose a diet higher in beneficial fats, plants and whole grains, said Orchard, who is part of Ohio State’s Food Innovation Center.

“This suggests that as women age, healthy diets are impacting their bones,” Orchard said. “I think this gives us yet another reason to support the recommendations for a healthy diet in the Dietary Guidelines for Americans.”

Because the study was observational, it’s not possible to definitively link dietary patterns and bone health and fracture outcomes.

Rebecca Jackson, the study’s senior author and director of Ohio State’s Center for Clinical and Translational Science, said the new findings support a growing body of evidence that factors that increase inflammation can increase osteoporosis risk.

“By looking at the full diet rather than individual nutrients, these data provide a foundation for studying how components of the diet might interact to provide benefit and better inform women’s health and lifestyle choices,” said Jackson, who is national chair of the Women’s Health Initiative steering committee.

Previous studies have connected high levels of inflammatory markers in the blood to bone loss and to fractures in older women and men, which prompted Orchard and her colleagues to wonder what they’d find if they took one more step back – to the dietary choices that contribute to inflammation in the body.

The Dietary Inflammatory Index – developed to assess the quality of diet from maximally to minimally inflammatory based on nutrients consumed – helped them accomplish that. Dietary information as well as data on bone density and fracture were collected from a large group of the participants in the Women’s Health Initiative, the largest study of postmenopausal women’s health undertaken in U.S. history.

Participants in the WHI were 50 to 79 when they enrolled in the study of prevention and control of common diseases impacting older women. Enrollment ran from 1993 to 1998.

For the new analysis – the first of its kind – the research team looked at dietary data from 160,191 women and assigned inflammation scores based on 32 food components that the women reported consuming in the three months prior to their enrollment.

The researchers used bone-mineral-density data from a subset of 10,290 women. Fracture data was collected for the entire study group.

Orchard and her colleagues found a correlation only between high-inflammatory diets and fracture in younger white women in the study. Higher scores were associated with an almost 50 percent larger risk of hip fracture in Caucasian women younger than 63, compared with the risk for women in the group with the lowest inflammatory scores.

“This suggests that a high-quality, less-inflammatory diet may be especially important in reducing hip fracture risk in younger women,” the researchers wrote.

But in the study group overall, more-inflammatory diets were not linked to fracture and – in fact – the researchers found a modestly lower risk of lower-arm and total fracture in women with the highest dietary inflammation scores. One possible explanation included in the study: The women with lower inflammation scores were more physically active as a group and therefore were at a slightly greater risk of falls.

Women with the least-inflammatory diets had lower bone mineral density overall at the start of the study, but lost less bone than their high-inflammation peers, the researchers found. The lower bone density to start could be because women with healthier diets are more likely to be of a smaller build, Orchard said. Larger people have higher bone density to support their larger frames.

“These women with healthier diets didn’t lose bone as quickly as those with high-inflammation diets, and this is important because after menopause women see a drastic loss in bone density that contributes to fractures,” Orchard said.

Public Release: 30-Jan-2017

Anticancer properties of mono/di-halogenated coumarins

This research article by Dr. Kabange Kasumbwe et al. has been published in Anti-Cancer Agents in Medicinal Chemistry, Volume 17, Issue 2, 2017

Bentham Science Publishers

Throughout the world, many medicinal compounds are being discovered. Scientists have learnt to modify the chemical structures of active compounds so that they can improved therapeutic activity and reduced the toxicity. In view of the established low toxicity, relative cheapness, presence in the diet, and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

Coumarins were first isolated from the plant species Dipteryx odorata Willd (Family: Fabaceae) in 1820. The name coumarin is derived from ‘Coumarou’. The French commonly called them Tonka beans (Dipteryx odorata Willd, Fabaceae), from which coumarins were derived.

Coumarins are naturally occurring plant metabolites known for their various pharmacological properties such as anticoagulant, antimicrobial, anticancer, antioxidant, anti-inflammatory and antiviral properties.

In the present investigation, mono/di-halogenated coumarins CMRN1-CMRN7 have been synthesized and evaluated for their anticancer activity. The cytotoxic potential of the test compounds was evaluated against UACC-62, MCF-7 and PBM (Peripheral Blood Mononuclear) cell lines using MTT assay. The apoptotic potential of the coumarin compounds was evaluated against UACC-62 cells by assessing membrane change, mitochondria membrane potential, pro-apoptotic changes were investigated using the Annexin V-PI staining, JC-1, caspase-3 enzyme kits respectively on a flow cytometer. The test compounds CMRN1, CMRN2, CMRN4 and CMRN5 have strongly suppressed the cell proliferation of UACC-62 and MCF-7 cancer cell lines. Furthermore the test compounds CMRN1, CMRN2, CMRN4 and CMRN5 exerted antiproliferative effects through apoptosis induction against UACC-62.

Public Release: 30-Jan-2017

Antibiotics can boost bacterial reproduction

University of Exeter

The growth of bacteria can be stimulated by antibiotics, scientists at the University of Exeter have discovered.

The EPSRC-funded researchers exposed E.coli bacteria to eight rounds of antibiotic treatment over four days and found the bug – which can cause severe stomach pain, diarrhoea and kidney failure in humans – had increased antibiotic resistance with each treatment.

This had been expected, but researchers were surprised to find mutated E.coli reproduced faster than before encountering the drugs and formed populations that were three times larger because of the mutations.

This was only seen in bacteria exposed to antibiotics – and when researchers took the drug away, the evolutionary changes were not undone and the new-found abilities remained.

“Our research suggests there could be added benefits for E.coli bacteria when they evolve resistance to clinical levels of antibiotics,” said lead author Professor Robert Beardmore, of the University of Exeter.

“It’s often said that Darwinian evolution is slow, but nothing could be further from the truth, particularly when bacteria are exposed to antibiotics.

“Bacteria have a remarkable ability to rearrange their DNA and this can stop drugs working, sometimes in a matter of days.

“While rapid DNA change can be dangerous to a human cell, to a bacterium like E.coli it can have multiple benefits, provided they hit on the right changes.”

The researchers tested the effects of the antibiotic doxycycline on E.coli as part of a study of DNA changes brought about by antibiotics.

The E.coli “uber-bug” that subsequently evolved was safely frozen at -80C and the scientists used genetic sequencing to find out which DNA changes were responsible for its unusual evolution.

Some changes are well known and have been seen in clinical patients, like E.coli producing more antibiotic pumps that bacteria exploit to push antibiotics out of the cell.

Another change saw the loss of DNA that is known to describe a dormant virus.

“Our best guess is that losing viral DNA stops the E.coli destroying itself, so we see more bacterial cells growing once the increase in pump DNA allows them to resist the antibiotic in the first place,” said Dr Carlos Reding, who was part of the study.

“This creates an evolutionary force for change on two regions of the E.coli genome.

“Normally, self-destruction can help bacteria colonise surfaces through the production of biofilms. You see biofilms in a dirty sink when you look down the plughole.

“But our study used liquid conditions, a bit like the bloodstream, so the E.coli could give up on its biofilm lifestyle in favour of increasing cell production.”

Dr Mark Hewlett, also of the University of Exeter, added: “It is said by some that drug resistance evolution doesn’t take place at high dosages but our paper shows that it can and that bacteria can change in ways that would not be beneficial for the treatment of certain types of infection.

“This shows it’s important to use the right antibiotic on patients as soon as possible so we don’t see adaptations like these in the clinic.”

Public Release: 31-Jan-2017

Yeast mutants unlock the secrets of aging

Two Concordia studies identify mechanisms that shorten longevity and can be targeted by natural chemicals to improve health and extend human lifespan

Concordia University

Montreal, January 31, 2017 — Yeast — it’s more than just a fungus. It can also tell us a lot about growing older.

That’s because aging in both human and yeast cells is not only the result of passive wear and tear. It’s also caused by an active process orchestrated by a distinct set of genes, some of which slow down aging while others speed it up.

In two recently published articles, Concordia biology professor Vladimir Titorenko from the Faculty of Arts and Science and a team of fellow researchers take a closer look into what these delaying and accelerating yeast genes might mean for humans.

“We’re the first to provide evidence for the existence of genetic mechanisms that limit lifespan,” Titorenko says.

For the studies, the researchers exposed yeast to lithocholic acid, an aging-delaying natural molecule that Titorenko discovered in a previous study. In so doing, they created long-lived yeast mutants that they dubbed “yeast centenarians.”

These yeast mutants lived five times longer than their normal counterparts because their mitochondria — the part of the cell responsible for respiration and energy production — consumed more oxygen and produced more energy than in normal yeast. The centenarians were also much more resistant to oxidative damage, which is another process that causes aging.

“This confirms that lithocholic acid, which occurs naturally in the environment, can not only delay yeast aging but can also force the evolution of exceptionally long-lived yeast,” Titorenko explains.

Reprogramming aging

The next step? Using yeast centenarians to test two types of aging theories:

1. Programmed aging theories claim that organisms are genetically programmed to have a limited lifespan because aging serves some evolutionary purpose. That would mean that there are active mechanisms that cause aging and limit lifespan.

2. Non-programmed aging theories contend that aging doesn’t serve an evolutionary purpose. Therefore, an evolved mechanism whose main goal is to cause aging or limit lifespan simply cannot exist. What’s more, non-programmed aging theories posit that any exceptionally long-lived organism must grow slower and reproduce less efficiently than an organism whose lifespan is limited at a certain age.

By producing long-lived yeast mutants and culturing them separately from normal yeast, Titorenko and his team were able to show that the centenarians grow and reproduce just as efficiently as the non-centenarians — thereby confirming programmed aging theories.

From Titorenko’s perspective, these findings are significant — for humans as well as yeast.

“By confirming that there are active mechanisms limiting the longevity of any organism, we provided the first experimental evidence that such lifespan-limiting active mechanisms exist and can be manipulated by natural molecules to delay aging and improve health.”

Public Release: 1-Feb-2017

Vitamin C may decrease the risk of atrial fibrillation after cardiac surgery

University of Helsinki

AF is a common cardiac rhythm disturbance that can lead to severe consequences such as stroke and heart failure. AF can be triggered by various stressful conditions and about 30% of patients undergoing cardiac operations suffer from post-operative AF.

Harri Hemilä from the University of Helsinki, Finland, and Timo Suonsyrjä from the Helsinki University Central Hospital, Finland, carried out a systematic review of vitamin C for preventing AF in high risk patients. They identified 14 randomized trials totaling 2006 patients who had undergone cardiac surgery, and one trial with 44 patients that had investigated the recurrence of AF after a successful cardioversion.

There was substantial heterogeneity between the 14 cardiac surgery trials, but the heterogeneity was explained by the division of them between five trials carried out in the USA and nine trials conducted outside of the USA. The five cardiac surgery trials carried out in the USA uniformly found no effect of vitamin C against post-operative AF. In contrast, the nine cardiac surgery trials conducted outside of the USA found a mean reduction of 44% in the incidence of post-operative AF and there was no heterogeneity between these nine trials. Five of the latter trials were carried out in Iran, two in Greece, one in Slovenia and one in Russia.

The single study on the recurrence of AF after a successful cardioversion, which was carried out in Greece, found that vitamin C decreased the risk of AF recurrence by 87%.

In the non-US cardiac surgery trials, vitamin C decreased the length of hospital stay by 12.6% and intensive care unit stay by 8.0%.

Some of the surgery patients in the non-US studies were administered vitamin C orally, whereas in others vitamin C was administered intravenously. The latter route leads to substantially higher levels of vitamin C in the blood, thus the effects of the two administration methods might differ.

Oral administration of vitamin C decreased the occurrence of post-operative AF by 73%, whereas intravenous administration decreased it by 36%. On the other hand, oral administration shortened the length of hospital stay by only 7% (0.4 days), whereas intravenous administration decreased it by 16% (1.5 days). Thus, the effect of intravenous vitamin C administration was greater for the length of hospital stay, but less for the occurrence of post-operative AF.

According to Drs. Hemilä and Suonsyrjä, “Vitamin C is a safe low-cost essential nutrient. Given the consistent evidence from the less wealthy countries, vitamin C might be administered to cardiac surgery patients, although further studies are needed to find out optimal protocols for its administration. However, there seems to be no rationale for further study of unselected patients in wealthy countries, but the effects of vitamin C for patients who have a particularly low documented level of vitamin C might still be worthwhile.”

Public Release: 1-Feb-2017

Vitamin D discovery could prove key to new treatments

Kyoto University

A team led by Motonari Uesugi, professor and deputy director of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS), found that a vitamin D metabolite known as ’25-OHD’ inhibits proteins that regulate lipid production. Those proteins, called sterol regulatory element-binding proteins (SREBPs), cannot then stimulate expression of lipid-producing genes.

“To our knowledge, this is the first demonstration that 25-OHD inhibits SREBPs,” the researchers concluded in their study recently published in Cell Chemical Biology.

Drug companies could develop synthetic analogs of 25-OHD to potentially help regulate lipid production in individuals who lack vitamin D to do this for them.

Vitamin D deficiency is caused by insufficient dietary intake or sunlight exposure, and it is increasing worldwide. It is associated with several bone diseases such as rickets in children and osteoporosis in adults. It is also linked with metabolic disorders and certain types of cancers. But it has been unclear how the lack of vitamin D contributes to metabolic disorders and cancers.

The research team came across 25-OHD while screening an extensive chemical library of endogenous molecules. They were looking for inhibitors of SREBPs, which regulate lipid production, and honed in on 25-hydroxyvitamin D (25-OHD), which is a hydroxylated vitamin D metabolite.

The relationship between 25-OHD and lipid levels has been known for more than 20 years. However, 25-OHD has generally been considered biologically inactive.

The researchers found 25-OHD induces the breakdown of SREBP cleavage-activating protein (SCAP), an escort protein required for SREBP activation. They were able to document how 25-OHD degrades SCAP into smaller amino acids.

SREBP and SCAP proteins are increasingly recognized as potential drug targets for cancers and metabolic disorders. Understanding the role 25-OHD plays in the SREBP-SCAP interaction and in lipid regulation could open up new treatment opportunities.

Public Release: 3-Feb-2017

Pilot study highlights role of grapes in preventing Alzheimer’s disease

Grape-enriched diet prevents metabolic brain decline, improves attention and memory

California Table Grape Commission

FRESNO, CA – Consuming grapes twice a day for six months protected against significant metabolic decline in Alzheimer-related areas of the brain in a study of people with early memory decline. Low metabolic activity in these areas of the brain is a hallmark of early stage Alzheimer’s disease. Study results showed a grape-enriched diet protected against the decline of metabolic activity. Additionally, those consuming a grape-enriched diet also exhibited increased metabolism in other areas of the brain that correlated with individual improvements in attention and working memory performance, compared to those on the non-grape diet. Results of the randomized controlled research study, conducted by the University of California, Los Angeles, were recently published in Experimental Gerontology[1].

“The study examines the impact of grapes as a whole fruit versus isolated compounds and the results suggest that regular intake of grapes may provide a protective effect against early decline associated with Alzheimer’s disease,” said Dr. Daniel H. Silverman, lead investigator of the study. “This pilot study contributes to the growing evidence that supports a beneficial role for grapes in neurologic and cardiovascular health, however more clinical studies with larger groups of subjects are needed to confirm the effects observed here.”

In the study, subjects with early memory decline were randomly selected to receive either whole grape powder – equivalent to just 2 ¼ cups of grapes per day – or a polyphenol-free placebo powder matched for flavor and appearance. Cognitive performance was measured at baseline and 6 months later. Changes in brain metabolism, assessed by brain PET scans, were also measured at baseline and 6 months later. PET scans provide valuable predictive and diagnostic value to clinicians evaluating patients with dementia symptoms.

The results showed that consuming grapes preserved healthy metabolic activity in the regions of the brain that are affected by the earliest stages of Alzheimer’s disease, where metabolic decline takes hold. Subjects who didn’t consume grapes exhibited significant metabolic decline in these critical regions. Additionally, those consuming the grape-enriched diet showed beneficial changes in regional brain metabolism that correlated to improvements in cognition and working memory performance.

Grape polyphenols help promote antioxidant and anti-inflammatory activities. Research suggests that grapes may help support brain health by working in multiple ways – from reducing oxidative stress in the brain to promoting healthy blood flow in the brain to helping maintain levels of a key brain chemical that promotes memory to exerting anti-inflammatory effects[2].

Alzheimer’s disease is a brain disease that results in a slow decline of memory and cognitive skills. Currently 5.4 million Americans are living with Alzheimer’s disease and the numbers continue to grow. The cause of Alzheimer’s disease is not yet fully understood, but believed to be a combination of genetic, environmental and lifestyle factors.